Biomarkers in epidemiology: scientific issues and ethical implications.

The current generation of biologic markers have three characteristics that differentiate them from previous ones. These include the ability to detect xenobiotics at concentrations at the cellular and molecular level, to detect earlier biologic changes presumptive of disease or disease risk, and to identify a detailed continuum of events between an exposure and resultant disease. If biomarkers are to enhance cancer epidemiology, they must be valid, reliable, and practical. When these characteristics have not been previously demonstrated, pilot studies should be conducted prior to the primary study. Interdisciplinary communication and collaboration is required so that useful markers are selected and that collection and handling, assay, and interpretation are appropriate. The status of many biomarkers is that they have been developed in the laboratory but lack validation for field use. Validation of a marker for use in a population requires attention to issues of background prevalence, sample size, natural history, persistence, variability, confounding factors, and predictive value. Additionally, practical features such as subject preparation, access to specimens, specimen storage aspects, and costs must be clarified. Ultimately, the use of biologic markers in epidemiologic studies will depend on how well the markers increase ability to reduce misclassification, provide for better interpretation of exposure-disease associations, and increase opportunities for prevention. Validation studies and general research using biomarkers also have clinical, ethical, and legal implications. These range from communicating uncertainty about the meaning of a marker to the kinds of societal response that result when groups or individuals are identified as having an "abnormal" marker frequency.